Penicillin and cephalosporin derivatives



United States Patent 3,382,238 PENICILLIN AND CEPHALOSPORIN DERIVATIVESJoseph E. Dolfini, North Brunswick, N.J., assignor to E. R. Squibb &Sons, Inc., New York, N.Y., a corporation of Delaware No Drawing. FiledApr. 27, 1967, Ser. No. 634,115 11 Claims. (Cl. 260-2391) ABSTRACT OFTHE DISCLOSURE This invention relates to novel therapeutic agentsrelated to penicillin and cephalosporin C. The compounds of thisinvention contain the penicillin and cephalosporin C chemical structuresubstituted at the 6- or 7-position, respectively with substituted alkylor aryl sulfinylaryl radicals.

These compounds possess a high degree of antibacterial activity againsta large number of microorganisms. In addition, the compounds of thisinvention are useful as animal feed supplements and as the activeingredient in germicidal preparations employed to disinfect walls,tables, and the like.

Detailed description This invention relates to novel therapeutic agentsrelated to penicillins and cephalosporin C and which have activity asantimicrobial agents.

Compounds of the present invention may be represented by the followingstructural formula Be .NH 3

i 0 wherein R is either if c 3 (II) I 3 CO H a or (In) /-ca -A wherein Ais a member selected from the group c0nsist ing of the acyloxy radicalof a hydrocarbon carboxylic acid of less than twelve carbon atoms, asexemplified by the lower alkanoic acids (e.g., acetic, propionic,butyric, valeric and caproic acid), the lower alkenoic acids (e.g.,Z-butenoic acids), the cycloalkanecarboxylic acids, thecycloalkenecarboxylic acids, the monocyclic aryl(lower alkanoic acids)(e.g., phenylacetic and fi-phenylpropionic acid), and the monocyclicaryl carboxylic acids (e.g., benzoic and p-toluic acid); a quaternaryammonium radical, e.g., tetramethylammonium, pyridinium, quinolinium,picolinium, etc.; amino; lower alkyl amino, such as ethyl amino orisopropylamino; di(lower alkyl)amino; monocyclic aryl-lower alkylamino;di(monocyclic aryl-lower alkyl)amino; heterocyclic tertiary amino suchas imidazolyl and piperidino; and when taken together with M.

a monovalent carbon-oxygen bond; and M is a member selected from thegroup consisting of hydrogen, a pharmaceutically acceptable nontoxiccation, an anionic charge when A is a quaternary ammonium radical, andwhen taken together with A, a monovalent carbon-oxygen bond; and R isrepresented by wherein R represents lower alkyl, monocyclic aryl ormonocyclic aryl-lower alkyl; R and R taken separately, each representhydrogen, lower alkyl, monocyclic aryl, or monocyclic aryl-lower alkyl;and n is 1, 2 or 3.

The term lower alkyl, as employed herein include both straight andbranched chain radicals of less than eight carbon atoms. Lower alkylgroups are exemplified by methyl, ethyl, propyl, isopropyl, n-butyl,1,1-dimethylbutyl and n-hexyl.

By monocyclic aryl is meant phenyl and substituted phenyl radicals suchas lower alkyl phenyl, as exempli fied by o-, m-, or p-tolyl andethylphenyl, di(lower alkyl) phenyl is exemplified by p-xylyl, loweralkoxyphenyl as exemplified by methoxyphenyl and propoxyphenyl andhalophenyl as exemplified :by chloro-, bromo-, iodoand fiuorophenyl.

As pharmaceutically acceptable cations may be mentioned metallic cationssuch as sodium, potassium, calcium and aluminum and organic aminecations such as trialkylamines, e.g., triethylamine, procaine,dibenzylamine, N-benZyl-fl-phenethylamine, l-ephenamine, N,N'-dibenzylethylenediamine, dehydroabietylamine,N,N'-bisdehydroabietylethylenediamine, N (lower)alkylpiperidines, e.g.,N-ethylpiperidine, quaternary ammonium ions (e.g., tetramethylammonium,tetraethylammonium, pyridinium and the like), and other amines whichhave been used to form salts with benzylpenicillin.

Particularly preferred compounds of this invention are those wherein Ais selected from the group consisting of acetoxy and pyridinium, and Mis selected from the group consisting of an alkali metal and, when A ispyridinium, an anionic charge.

Compounds of this invention (i.e., the compounds of Formula I) arephysiologically active substances which have a high degree ofantibacterial activity against a large number of microorganisms,including Gram positive and Gram negative microorganisms such asStaphylococcus, aureus, Escherichia coli, Klebsiella pneumoniwe,Aerabacter aerogenes, and Shigella sonnei.

For these purposes, they may be administered orally or parenterially insuch form as tablets, capsules, injectables, or the like byincorporating the appropriate dosage of the compound with carriersaccording to standard pharmaceutical practices. Dosages for variousmammillary species (e.g., rats, dogs, cats, cattle, horses, etc.) wouldbe from about 0.01 to about 1.5 gm./kg. daily, administered once toseveral times a day.

In addition, the compounds of this invention are useful as supplementsto animal feeds, such as for poultry, cattle and swine (particularlymeanling pigs) as an aid in increasing growth rate, improved feedefficiency, and in the suppression of infections during periods ofstress, such as weaning, castration, vaccination, high temperature andmoving. For such purposes the concentration in the ani mal feed wouldrange from about 10 to 400 grams per ton, optimally about 200 grams perton.

Further, the compounds of this invention, in aqueous solution orsuspension, may be employed as disinfectants against variousstaphylococci. For this purpose, they are dissolved or suspended inwater, preferably also containing a detergent, at a concentration ofabout 0.5% to 3 about 10% and may be used as washes to disinfect walls,floors, tables and the like.

Compounds in accordance with Formula I are prepared by coupling ofalkylsulfinylcarboxylic acids having the formula R o R. i-[t] 30..

wherein R R and R are as set forth above, with amino compounds havingthe formula ing the formula 0 R o R. t [3] t (VII) wherein R R R and nare as set forth hereinabove and B represents halogen, azide orp-nitrophenoxy, employing the appropriate reagents in known fashion(Bodanszky and Ondetti, op. cit.). Compounds obtained according toFormula VII are then reacted with the amino compound of Formula VI inthe presence of a base such as pyridine, triethylamine or sodiumbicarbonate to provide compounds of this invention in accordance withFormula I.

Those compounds in accordance with Formula I wherein R is represented byFormula III and A is other than acetoxy are generally prepared from theacetoxy derivative by nucleophilic displacement of the acetoxy group bythe appropriate group. For example, a compound in accordance withFormula I wherein R is III and A is acetoxy may be reacted with, forinstance, pyridine, under aqueous conditions at 35 to 45 C. at a pH ofabout 5 to 8. Alternatively, of course, compounds in accordance withFormula VI may be converted to the desired derivatives in the abovemanner and then subjected to the described coupling reaction to formfinal products of this invention under aqueous conditions at 35 to 45 C.at a pH range of 5 to 8.

Derivatives in accordance with Formula I wherein A and M are takentogether forming a rnonovalent carbonoxygen bond may be prepared by acidhydrolysis of compounds according to either Formulas I or VI, wherein Ais acetoxy, to form a 7-substituted 3-hydr0xy methyldecephalosporanicacid lactone.

Alternatively, enzymatic hydrolysis of compounds of Formula I or VI,wherein A is acetoxy may provide 7 -substituted deacetyl cephalosporanicacid, wherein A is hydroxy, and these hydroxy compounds may be caused toform the lactones by acid treatment.

As indicated, these reactions may be performed either before or afterthe coupling reaction in forming products in accordance with thisinvention.

Compounds according to Formula V are prepared by the oxidation of thecorresponding sulfides of the type by treatment with peracids such asm-chloroperbenzoic acid or by hydrogen peroxide, either in admixturewith benzene, acetic acid, methylene chloride or mixtures thereof.

The sulfides Va are obtained from the equirnolar amounts of halides ofthe type R X with mercaptoacids having the formula 34 H-s- -CO:H

in the presence of at least two moles per mole of reactants of a base,such as aqueous sodium hydroxide, alcoholic potassium hydroxide orpotassium t-butoxide, in dimethylformamide at ambient temperatures.

Among the halides of the type R X may be mentioned: iodomethanebromoethane l-iodohexane l-chloro-3,3-dimethylpentaneZ-iodo-l-(iodomethyl)benzene 1-chloro-2-phenylethane1-chlor0-2-me'thyl-2-phenylethane 2-chloro-2- 4-chlorophenyl ethane1-i0do-3-(4-methoxyphenyl)propane.

Among the mercapto acids of Formula Vb may be mentioned:

Z-mercaptoethanoic acid Z-mercaptopropanoic acid 4-mercaptohexanoic acid3-mercaptononanoic acid 2-mercapt0-5,S-dimethylhexanoic acid2-mercapto-3,3-dimethylbutanoic acid 2-mercapto-2-phenylethanoic acid2-mercapto-2-(4-tolyl)ethanoic acidZ-mercapto-Z-(Z-methoxyphenyl)ethanoic acid2mercapto-2-(4-ethylphenyl)ethanoic acid2-mercapto-2-(4-chlorophenyl)ethanoic acid2-mercapto-2-(2,4-dibromopheny1)ethanoic acid3-mercapto-3-phenylpropanoic acid2-mercapto-3-(4-methoxyphenyl)pentanoic acid4-mercapto-6-(2-tolyl)hexanoic acid2-mercapto-3,3-dimethyl-4-(4-fiuorophenyl)butanoic acid2-unercapto-2-methylpropanoic acid 2-mercapto-Z-ethylbutanoic acid3-mercapto-2-propylhexanoic acid 2-mercapto-2-ethyl-3,3-dimethylbutanoicacid Z-mercapto-Z-phenylpropanoic acid2-mercapto-2-(2,4dimethoxyphenyl)-3-methylpentan0ic acid 2-mercapto-2-(3-chlorophenyl)butanoic acid 3-mercapto-2-(2,4,6-trimethylphenyl)propanoic acid 2-mercapto-2-ethyl-6- (4-methoxyphenyl hexanoic acid2-mercapto-2-isopropyl-4- 3-chlorophenyl -6,6-dirnethylheptanoic acidZ-mercapto-Z-methyl-3-phenylpropanoic acid2-mercapto-2-(p-xylyl)butanoic acid 2-mercapto-2,Z-diphenylethanoic acid2-mercapto-2-phenyl-2-(p-xylyl)ethanoic acid2-mercapto-2,2-di(4-chlorophenyl)ethanoic acid 2-mercapto-2-3-propoxy-phenyl -2- 3 ,S-dimethylphenyl) ethanoic acid2-mercapto-2,3-diphenylpropanoic acid2-mercapto-2-phenyl-3,3,4,4-tetramethyl-S-phenyl-pentanoic acid2-mercapto-2-phenyl-4- (4-methoxyphenyl)butanonic acid2-mercapto-2-(2,4-dimethoxypheny1)-3-(4-iodophenyl) propanoic acid2-mercapto-2-benzyl-3-phenylpropanoic acid 2-mercapto-2- a-methylbenzyl-3,3,4-trimethyl-4-phenylpentanoic acid2-mercapto-2-(Z-methoxybenzyl)-4-(4-fluorophenyl) butanoic acid4-mercapto-2-(p-xy'lyl)-fi-phenylhexanoic acid.

Alternatively, the sulfides Va are obtained by equimolar reaction ofmercaptans of the type R SH with haloacids of the type 34 X- C02H lamethanethiol ethanethiol prop anethiol t-butanethiol l-hexanethiol3,3-dimethylpentanethiol benzenethiol 2-chlorobenzenethiol4-chloro-benzenethiol Z-fluorobenzenethiol 4-fluorobenzenethiol2-bromobenzenethiol 3,5-dichlorozenethil 2,4,6-trifiuorobenzenethiolo-toluenethiol p-toluenethiol 2,4-dimethylbenzenethiol2-ethylbenzenethiol 4-n-propylbenzenethiol 4-t-butylbenzenethiol4-n-hexylbenzenethiol Z-methoxybenzenethiol 4-methoxybenzenethiol3,S-dirnethoxybenzenethiol 4-etheoxybenzenethiol 4-pr0poxybenzenethio1benzenemethanethiol o-methylbenzenemethanethiola-methylbenzeneethanethiol a-methyl-p-chlorobenzenemethanethiol3-(p-methoxy-benzene)propane-l-thiol.

Among the haloacids having the Formula Vc may be mentioned:

2-chloroethanoic acid Z-bromohexanoic acid 2-iodononanoic acid2-chloro-5,5-dimethylhexanoic acid 2-bromo-3,3-dimethylbutauoic acid2-chloro-2-phenylethanoic acid 2-bromo-2- (Z-methoxyphenyl) ethanoicacid 2-iodo-2- (4-ethylphenyl) ethanoic acid 2-chloro-2-(4-chlorophenyl)ethancic acid 2-bromo-2-'(2,4-dibromophenyl)ethanoic acid2-chloro-3-phenylpropanoic acid 2-bromo-3-(4-methoxyphenyl)pentanoicacid 2-iodo-6-(2-tolyl) hexanoic acid 2-chloro-2-methylpropanoic acid2-bromo-2-ethylbutanoic acid 2-iodo-2-ethyl-3,3-dimethylbutan0ic acidZ-chloro-2-phenylpropanoic acid2-bromo-2-(2,4-dimethoxyphenyl)-3-methylpentanoic acid2-iodo-2-(2,4,6-trimethylphenyl) propanoic acid3-chloro-2-ethyl-6-(meth0xyphenyl)hexanoic acid 5-bromo-2-isopropyl-4-3-chlorophenyl -6,6-dimethylheptanoic acid 3-iodo-2-(p-xylyl)butanoicacid 2-chloro-2,Z-diphenylethanoic acid2-bromo-2-pheuyl-2-(p-xylyl)ethanoic acid 2-iodo-2- 3 -propoxypher1yl-2-( 3,5 -dimethylphenyl) ethanoic acid 2-chloro-2,3-diphenylpropanoicacid 2-bromo-2-pheny1-3,3,4,4-tetramethyl-5-phenyl-pentanoic acid2-iodo-2-(2,4-dirnethoxypheny1)-3-(4-iodophenyl)propanoic acid2-chloro-2-benzyl-3-phenylpropanoic acid 2-bromo-2- a-methylbenzyl-3,3,4-trimethyl-4-phenylpentanoic acid 4-iodo-2- p-xylyl-6-phenylhexanoic acid.

The following examples illustrate the invention. All

temperatures are in degrees centigrade unless otherwise stated. I

EXAMPLE 1 7- 3- (methyls ulfinyl propionamido] cephalosporanic acid,potassium salt A solution of 2.72 g. of 7-aminocephalosporanic acid and0.84 g. sodium bicarbonate in a solution of 30 ml. of water and 30 ml.of acetone (or 60 ml. dimethylformamide may be used as the solvent) istreated with 1.06 g. of 3-(methylsulfinyl)propionic acid and 2.06 g.dicyclohexylcarbodiimide. After stirring the reaction mixture at roomtemperature for three hours, the precipitated dicyclohexylurea isfiltered 05. The solution is diluted with 100 m1. of ice water,acidified with dilute hydrochloric acid, and extracted with 3x 50 :ml.CHC1 The chloroform extract is dried (MgSO filtered and evaporated atreduced pressure. The residual cephalosporin C derivative is taken up inethanol and treated with an equivalent of aqueous KOH. The potassiumsalt of the product is obtained in crude form by evaporation and ispurified by crystallization from aqueous acetone or alcohol.

EXAMPLE 2 6- 3- (methylsulfinyl) propionamido]penicillanic acid,potassium salt Substitution of 2.16 g. of 6-aminopenicillanic acid forthe 7-aminocephalosporanic acid in Example 1 leads to the penicillinderivative as the potassium salt.

EXAMPLE 3 7- 3 phenylsulfinyl propionamido] cephalosporanic acid,potassium salt Following the procedure of Example 1 but substituting anequivalent amount of 3-(phenylsulfinyl)propionic acid for theB-methylsulfinylpropionic acid, the desired product is obtained.

EXAMPLE 4 7- [Z-methylsulfinyl) -2-methylpropionamido] cephalosporanicacid, potassium salt Following the procedure of Example 1 butsubstituting an equivalent amount of2-(methylsulfinyl)-2-methylpropionic acid for the3-methylsulfinylpropionic acid, the desired product is obtained.

EXAMPLE 5 7-I4-methylsulfinyl)-3-phenylbutyramido]cephalosporanic acid,potassium salt Following the procedure of Example 1 but substituting anequivalent amount of 4-(methylsulfinyl)-3-phenylbutyric acid for the3-(methylsulfinyl)propionic acid, the desired product is obtained.

EXAMPLE 6 7- [2-benzyl-3- (ethylsulfinyl propionamido] cephalosporanicacid, potassium salt Following the procedure of Example 1 butsubstituting an equivalent amount of 2-benzyl-3-(ethylsulfinyl)propionic acid for the 3-(methylsulfinyDpropionic acid, the desiredproduct is obtained.

EXAMPLE 7 7- 3- ethylsulfinyl propionamido] cephalosporanic acid,potassium salt A solution of 1.50 g. of 3-(ethylsulfinyl)propionic acidand 1.01 g. of triethylamine in 50 ml. of acetonitrile is treated with1.10 g. of ethyl chloroformate for 20 minutes at C. The resultingmixture is then treated with a mixture of 2.72 g. of7-aminocephalosporanic acid and 1.01 g. of triethylamine in 50 ml. ofacetonitrile precooled to 0 C. The resulting reaction mixture is stirredat 0 C. for two hours, then diluted with 200 ml. of ice water, acidifiedwith dilute hyrochlorie acid and extracted with 4X 50 ml. chloroform.The chloroform extracts are dried (Na SO filtered, and evaporated atreduced pressure. The residual crude product is taken up in ethanol (ca.25 ml.) and treated with an equivalent of aqueous potassium hydroxide.The resulting potassium salt may be purified by crystallization fromaqueous acetone or alcohol.

EXAMPLE 8 6- 3-ethylsulfinyl) propionamido] penicillanic acid, potassiumsalt Substitution of 2.16 g. of 6-aminopencillanic acid for the7-aminocephalosporanic acid in Example 7 leads to the penicillinderivative as its potassium salt.

EXAMPLE 9 7- [2,3-diphenyl-2-(propylsulfinyl)propionamido]cephalosporanic acid, potassium salt Following the procedure of Example7 but substituting an equivalent amount of2,3-diphenyl-2-(propylsulfinyl) propionic acid for the 3(ethylsulfinyl)propionic acid, the desired product is obtained.

EXAMPLE 10 7-[3-benzyl-3-methyl-4-(benzylsulfinyl)butyramido]cephalosporanic acid, potassium salt Following the procedure of Example7 but substituting an equivalent amount of 3-benzyl-3-methyl 4(benzylsulfinyl)butyric acid for the 3-(ethylsulfinyl)propionic acid,the desired product is obtained.

EXAMPLE 11 6- [3-benzylsulfinyl) propionamido] pinicillanic acid,potassium salt A solution of 1.98 g. of 3-benzylsulfinylpropionic acid[obtained by peroxide oxidation of 3-(benzylthio)propionic acid], 1.3 g.of p-nitrophenol and 2.06 g. of dicyclohexylcarbodiimide in 50 ml. ofethyl acetate is stirred for one hour at room temperature. The solutionis then filtered and evaporated at reduced pressure. The crudep-nitrophenyl ester is taken up in 30 ml. of dioxane and added to asolution of 2.16 g. of fi-aminopencillanic acid and 1.01 g.triethylamine in 50 ml. dioxane. The resulting mixture is stirredovernight at room temperature, and then evaporated at reduced pressure.The gummy residue is partitioned between 3% aqueous hydrochloric acidand chloroform. The chloroform solution is dried (Na SO filtered andevaporated at reduced pressure. The residue of crude product is taken upin ethanol and treated with an equivalent of aqueous potassiumhydroxide. The resulting potassium salt may be recrystallized fromaqueous acetone or ethanol.

EXAMPLE l2 7 3- (benzylsulfinyl propionamido] cephalosporanic acid,potassium salt Use of 2.72 g. of 7-aminoceph-alosporanic acid in placeof the 6-aminopenicillanic acid in Example 11 gives the potassium saltof the penicillin derivative.

EXAMPLE 13 6- [Z-ethylsulfinyl -2-methylpropionamido] penicillanic acid,potassium salt Following the procedure of Example 11 but substituting anequivalent amount of Z-(ethylsulfinyl)-2-methylpropionic acid for the3-(benzylsulfinyl)propionic acid, the desired product is obtained.

8 EXAMPLE 14 6- 3- (benzylsulfinyl )butyramido] penicillanic acid,potassium salt Following the procedure of Example 11 but substituting anequivalent amount 3-(benzylsulfinyl)butyric acid for the3-benzylsulfinylpropionic acid, the desired product is obtained.

EXAMPLE 15 6- [2-methyl-2- (phenethylsulfinyl propionamido] penicillanicacid, potassium salt Following the procedure of Example 11 butsubstituting an equivalent amount of 2-methyl 2(phenethylsulfinyl)propionic acid for the 3-(benzylsulfinyl)propionicacid, the desired product is obtained.

EXAMPLE l6 7-[3-(methylsulfinyl)propionamido] -3-( l-pyridiniummethyl)-ceph-3-em-4-carboxylate A solution of 1.0 g. of 7-[3(methylsulfinyl)propionamidoJcephalosporanic acid and 0.5 ml. ofpyridine in 30 ml. of water is stirred at 35-45 C. for 14 hours and thenis freeze dried to give the crude product. Purification is effected bypassing an aqueous solution of the crude product through an ion exchangecolumn using Amberlite IRC-SO (acid form).

EXAMPLE 17 7- 3- methylsulfinyl propionamido] -3-(l-methylammoniummethyl) ceph-3-em-4-carboxylate Following the procedureof Example 16 but substituting equivalent amounts of methylamine for thepyridine, there is obtained the desired product.

EXAMPLE 18 7 -[3-methylsulfinyl)propionamido] -3-(l-diethylammoniummethyl) -ceph-3-em-4-carboxylate Following theprocedure of Example 16 but substituting equivalent amounts ofdiethylamine for the pyridine, there is obtained the desired product.

EXAMPLE 19 7-[3- (methylsulfinyl)propionamido] -3-(l-phenylammoniummethyl) -ceph-3-em-4-carb0xylate Following the procedureof Example 16 but substituting equivalent amounts of aniline for thepyridine, the desired product is obtained.

EXAMPLE 2O 7- [2-methyl-2- (methylsulfinyl) propionamido] deacetylcephalosporanic acid To a solution of 1.0 g. of 7-[2 methyl 2(methylsulfonyl)propionamido]cephalosporanic acid as the sodium salt in10 ml. of water at 30 C. is added 4.0 ml. of orange peel (citrus) acetylesterase solution [Jelfery et al., Biochem. J., 81, 591 (1961)] and thepH kept at 6.6 by automatic addition of N/ 10 aqueous sodium hydroxide.After the consumption of 0.95 equivalent of sodium hydroxide, themixture is freeze dried to provide the crude product, sodium salt. Thisis sufiiciently pure for further conversion.

EXAMPLE 217-[2-methyl-2-(methylsulfinyl)propionamidoJ-3-benzoyloxymethyl-ceph-3-em-4-carboxylateTo a solution of 400 mg. of 7-[2 methyl 2(methylsulfinyl)propionamido]-3-hydroxymethyl ceph 3-em- 4-carboxylate,sodium salt in 5 ml. of redistilled dimethylformamide at 10; 5 C. isadded benzoyl chloride, 154 mg., in 4 ml. of dirnethylformamide over a15 minute interval. The resulting solution is stirred for two hours andthen poured into an excess of 30 ml. of ice cold 2.5% aqueous sodiumbicarbonate solution. After working with 3X 15 ml. chloroform, theaqueous solution is acidified and the product extracted with 2x 15 ml.of chloroform. After drying (Na SO and filtering the product solutionevaporation at C. by vacuum gives the product as an amorphous powder.

The carboxylic acid is converted to its sodium salt by adding anequivalent amount of aqueous N/ 10 sodium hydroxide to a solution of thecrude acid in alcohol; dilution with ether and chilling induces theprecipitation of the sodium salt.

EXAMPLE 22 7- [2-methyl-2- (methylsulfinyl propionamido] deacetylcephalosporanic acid lactone o R o all elem LIIa n N( \C om on; (102Mwherein M is a member selected from the group consisting of hydrogen anda pharmaceutically acceptable nontoxic cation, R is selected from thegroup consisting of lower alkyl, monocyclic carbocyclic aryl andmonocyclic carbocyclic aryl-lower alkyl, R and R are each selected fromthe group consisting of hydrogen, lower alkyl, monocyclic carbocyclicaryl and monocyclic carbocyclic aryllower alkyl and n is 1, 2, or 3.

2. A therapeutically active compound having the formula wherein A is amember selected from the group consisting of the acyloxy radical of ahydrocarbon carboxylic acid of less than twelve carbon atoms; aquaternary ammonium radical; amino, lower alkyl amino; di(loweralkyl)amino; monocyclic carbocyclic aryl-lower alkyl amino; imidazolyland piperidino; and when taken together with M, a monovalentcarbon-oxygen bond; and M is a member selected from the group consistingof hydrogen, a pharmaceutically acceptable non-toxic cation, an anioniccharge when A is a quaternary ammonium radical, and when taken togetherwith A, a monovalent carbon-oxygen bond; and wherein R, R R and n are asset forth in claim 1.

3. A compound in accordance with claim 2 wherein A is selected from thegroup consisting of acetoxy and pyridinium and M is selected from thegroup consisting of an alkali metal and when A is pyridinium, an anioniccharge.

4. A compound in accordance with claim 2 having the name7-[3-(methylsulfinyl)propionamido]cephalosporanic acid, potassium salt.

5. A compound in accordance with claim 1 having the name 6 [3(methylsulfinyl)propionamido]penicillanic acid, potassium salt.

6. A compound in accordance with claim 2 having the name 7-[3(ethylsulfinyl)propionamido] cephalosporanic acid, potassium salt.

7. A compound in accordance with claim 1 having the name6-[3-(ethylsulfinyl)propionamido]penicillanic acid, potassium salt.

8. A compound in accordance with claim 1 having the name6-[3-(benzylsu1finyl)propionamido]penicillanic acid, potassium salt.

9. A compound in accordance with claim 2 having the name7-[3-(benzylsulfinyl)propionamido] cephalosporanic acid, potassium salt.

10. A compound in accordance with claim 2 having the name 7-[3(methylsulfinyl)propionamido] 3 (1- pyridinium-methyl) -ceph-3-em-4-carboxylate.

11. A compound in accordance with claim 2 having the name 7-[2(methylsulfinyl) 2 methylpropionamido] cephalosporanic acid, sodiumsalt.

References Cited UNITED STATES PATENTS 3,335,136 8/1967 Flynn 260-243NICHOLAS S. RIZZO, Primary Examiner.

